# Role of Histone Deacetylase 4 in Alcoholic Liver Disease

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT STORRS · 2021 · $231,438

## Abstract

PROJECT SUMMARY
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. ALD is the eighth most
common cause of mortality in the U.S. and the second leading cause of death among all gastrointestinal
diseases. Alcoholic hepatitis (AH) is the progressive form of ALD, which can progress to cirrhosis and
hepatocellular carcinoma. Therefore, there is an unmet need for developing effective therapeutic strategies for
AH. Evidence suggests histone deacetylases (HDACs) are involved in alcohol-induced cell damages. However,
little is known about the role of each HDAC isoform in the pathogenesis of AH. We found that HDAC4 mRNA
and protein levels were markedly increased in the human liver with alcoholic cirrhosis and the mouse
liver exposed to alcohol. Furthermore, our preliminary data indicate that ethanol increased HDAC4
expression in Huh-7 cells, a human hepatocellular carcinoma cell line. Also, ethanol induced the expression
of Hdac4 with concomitant increases in inflammation and oxidative stress in macrophages, which was
significantly attenuated when Hdac4 was knocked out or down. Sirtuin 1 (SIRT1) is known to prevent
alcohol-related cell damages and liver injury. Consistently, we found that a SIRT1 inhibitor increased
interleukin-1b (Il1b) expression, whereas a SIRT1 activator significantly abolished ethanol-induced
Hdac4 and Il1b expression in macrophages. It is of interest that Hdac4 deficiency increased Sirt1
expression, while human HDAC4 overexpression elicited the opposite effects in RAW 264.7
macrophages. The preliminary results suggest the HDAC4/SIRT1 axis may play a crucial role in the
development of AH. Based on the strong premise described above, we establish the central hypothesis that
the deletion of Hdac4 in hepatocytes or macrophages inhibits the development of AH by altering hepatic
expression of genes, including SIRT1, that are critically involved in alcohol-induced inflammation and oxidative
stress. We will take both targeted (SIRT1 pathway) and untargeted approaches (genome-wide transcriptome
analysis) using novel mice that have hepatocyte- or macrophage-specific deletion of Hdac4 under chronic-binge
ethanol feeding (the NIAAA model) as in vivo models. We will test the hypothesis by pursuing the following two
Specific Aims: 1) to determine the role of hepatocyte and macrophage HDAC4 in the development of AH and
to evaluate the HDAC4/SIRT1 axis for the pathogenesis of AH; and 2) to conduct a genome-wide transcriptome
analysis to identify HDAC4-regulated genes in hepatocytes and macrophages that mediate the pathogenic
processes of AH and to corroborate the findings using human liver specimens and primary human hepatocytes
and macrophages. The findings from this exploratory study will produce much-needed information on the role of
hepatocyte and macrophage HDAC4 in the pathogenesis of AH. Also, this study will lead to the discovery of new
genes/pathways, which can be exploited for future therapies for AH. Ther...

## Key facts

- **NIH application ID:** 10218894
- **Project number:** 1R21AA027310-01A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Ji-Young Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,438
- **Award type:** 1
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218894

## Citation

> US National Institutes of Health, RePORTER application 10218894, Role of Histone Deacetylase 4 in Alcoholic Liver Disease (1R21AA027310-01A1). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10218894. Licensed CC0.

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